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In vivo assay of human NK-dependent ADCC using NOD/SCID/gammac(null) (NOG) mice
Miho Shiokawa1, Takeshi Takahashi, Akihiro Murakami
1Department of Microbiology and Immunology, Tohoku University Graduate School of Medicine, 2-1 Seiryo-cho, Aoba-ku, Sendai 980 8575, Japan.
Abstract:
Monoclonal antibodies are essential to the success of molecularly targeted therapies. Recently, numerous therapeutic antibodies have been developed for various diseases, including cancer and autoimmune diseases. Experimental systems to effectively evaluate these candidate antibodies are urgently needed. One of the mechanisms used by antibodies to kill tumor cells is antibody-dependent cellular cytotoxicity (ADCC), in which natural killer cells (NK) are the main mediator. The capacity to induce ADCC has conventionally been assessed in the human-mouse xeno-graft model, in which human peripheral blood mononuclear cells (PBMC), containing NK cells along with antibodies, are administered to tumor-bearing immunodeficient mice. However, contamination from other cellular populations often affects tumor growth, making it difficult to evaluate the antibody's effect. In this study, we established a new NK-dependent ADCC assay model using a supra-immunodeficient strain of mice, NOD/SCID/gammac(null) (NOG). Our model system simply consisted of three elements: isolated human NK cells, a Burkitt's lymphoma cell line (Daudi), and an anti-CD20 antibody (Rituximab). In this experimental setting, human NK cells from healthy donors retained their killing activity and suppressed the growth of Daudi cells in NOG mice when they were administered along with Rituximab. This system, therefore, is useful for evaluating the in vivo function of human NK cells.
Insights
A novel mouse model using NOG mice effectively evaluates therapeutic antibodies. This system assesses antibody-dependent cellular cytotoxicity (ADCC) mediated by human natural killer (NK) cells, crucial for targeted cancer therapies.
Area of Science:
- Immunology
- Pharmacology
- Oncology
Background:
- Therapeutic monoclonal antibodies are vital for targeted therapies, particularly in cancer and autoimmune diseases.
- Evaluating antibody efficacy, especially their role in antibody-dependent cellular cytotoxicity (ADCC), requires robust experimental models.
- Existing human-mouse xenograft models have limitations due to cellular contamination affecting tumor growth and antibody assessment.
Purpose of the Study:
- To establish a new, reliable NK-dependent ADCC assay model for evaluating therapeutic antibodies in vivo.
- To overcome the limitations of conventional xenograft models in assessing antibody-mediated cellular cytotoxicity.
Main Methods:
- Utilized a supra-immunodeficient NOD/SCID/gammac(null) (NOG) mouse strain.
- Developed a simplified model comprising isolated human natural killer (NK) cells, Daudi (Burkitt's lymphoma) cells, and Rituximab (anti-CD20 antibody).
- Administered human NK cells and Rituximab to NOG mice bearing Daudi cells to assess NK cell activity and ADCC induction.
Main Results:
- Human NK cells from healthy donors maintained their cytotoxic activity within the NOG mouse model.
- The presence of Rituximab enhanced NK cell-mediated killing of Daudi cells.
- The model demonstrated suppressed tumor growth, indicating effective ADCC activity.
Conclusions:
- The established NOG mouse model provides a simplified and effective platform for evaluating the in vivo function of human NK cells and therapeutic antibodies.
- This model is particularly useful for assessing the ADCC-inducing capacity of novel antibodies in a controlled environment.
- The findings support the utility of this system for preclinical assessment of immunotherapies targeting tumors via NK cell activation.
